ClinVar Miner

Submissions for variant NM_005751.4(AKAP9):c.8677G>C (p.Asp2893His) (rs142573103)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000529741 SCV000627763 uncertain significance Long QT syndrome 2017-11-20 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 2893 of the AKAP9 protein (p.Asp2893His). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs142573103, ExAC 0.08%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with AKAP9-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786278 SCV000925035 uncertain significance not provided 2018-02-06 no assertion criteria provided provider interpretation Found in a 23-year-old female with unexplained postpartum sudden cardiac arrest, along with 5 other VUSs. p.Asp2893His (c.8677G>C) in exon 34 of the AKAP9 gene (NM_005751.4; ENST00000356239.7) Chromosome location 7:91713984 G / C Based on the information reviewed below, including the lack of case data and its prevalence in population databases, we classify it as a Variant of Uncertain Significance (VUS), probably benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for diagnosis or predictive genetic testing. This variant has not been reported in the literature in association with disease, according to the Invitae report. This is a nonconservative amino acid change, resulting in the replacement of a negatively-charged Aspartic Acid with a positively-charged Histidine. Aspartic Acid at this location is poorly conserved across ~100 vertebrate species for which we have data. There are no Likely Pathogenic or Pathogenic variants listed in ClinVar within 10 amino acids to either side, indicating that this region of the protein might be tolerant of change. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant was reported in 20 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Overall MAF: 0.007%. Invitae reports that it has an allele count higher than expected for a pathogenic variant. Of note: Whiffin et al (2017) proposed that variants with frequency greater than 0.0008% are unlikely to be pathogenic for LQTS. This variant was observed in 15 African-ancestry individuals (for the highest allele frequency: 0.06%) and 5 Latinos, (MAF 0.01%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. Our patient's ancestry is Latino.

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